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Journal of Translational Medicine Feb 2024Myasthenia gravis (MG) and the experimental autoimmune MG (EAMG) animal model are characterized by T-cell-induced and B-cell-dominated autoimmune diseases that affect... (Review)
Review
BACKGROUND
Myasthenia gravis (MG) and the experimental autoimmune MG (EAMG) animal model are characterized by T-cell-induced and B-cell-dominated autoimmune diseases that affect the neuromuscular junction. Several subtypes of CD4 T cells, including T helper (Th) 17 cells, follicular Th cells, and regulatory T cells (Tregs), contribute to the pathogenesis of MG. However, increasing evidence suggests that CD8 T cells also play a critical role in the pathogenesis and treatment of MG.
MAIN BODY
Herein, we review the literature on CD8 T cells in MG, focusing on their potential effector and regulatory roles, as well as on relevant evidence (peripheral, in situ, cerebrospinal fluid, and under different treatments), T-cell receptor usage, cytokine and chemokine expression, cell marker expression, and Treg, Tc17, CD3CD8CD20 T, and CXCR5 CD8 T cells.
CONCLUSIONS
Further studies on CD8 T cells in MG are necessary to determine, among others, the real pattern of the Vβ gene usage of autoantigen-specific CD8 cells in patients with MG, real images of the physiology and function of autoantigen-specific CD8 cells from MG/EAMG, and the subset of autoantigen-specific CD8 cells (Tc1, Tc17, and IL-17IFN-γCD8 T cells). There are many reports of CD20-expressing T (or CD20 + T) and CXCR5 CD8 T cells on autoimmune diseases, especially on multiple sclerosis and rheumatoid arthritis. Unfortunately, up to now, there has been no report on these T cells on MG, which might be a good direction for future studies.
Topics: Animals; Humans; CD8-Positive T-Lymphocytes; T-Lymphocytes, Helper-Inducer; Myasthenia Gravis, Autoimmune, Experimental; T-Lymphocytes, Regulatory; Autoantigens
PubMed: 38378668
DOI: 10.1186/s12967-024-04965-7 -
Immunology and Cell Biology May 2021One hundred years ago, Frederick Banting, John Macleod, Charles Best and James Collip, and their collaborators, discovered insulin. This discovery paved the way to... (Review)
Review
One hundred years ago, Frederick Banting, John Macleod, Charles Best and James Collip, and their collaborators, discovered insulin. This discovery paved the way to saving countless lives and ushered in the "Insulin Era." Since the discovery of insulin, we have made enormous strides in understanding its role in metabolism and diabetes. Insulin has played a dramatic role in the treatment of people with diabetes; particularly type 1 diabetes (T1D). Insulin replacement is a life-saving therapy for people with T1D and some with type 2 diabetes. T1D is an autoimmune disease caused by the T-cell-mediated destruction of the pancreatic insulin-producing beta cells that leads to a primary insulin deficiency. It has become increasingly clear that insulin, and its precursors preproinsulin (PPI) and proinsulin (PI), can play another role-not as a hormone but as an autoantigen in T1D. Here we review the role played by the products of the INS gene as autoantigens in people with T1D. From many elegant animal studies, it is clear that T-cell responses to insulin, PPI and PI are essential for T1D to develop. Here we review the evidence that autoimmune responses to insulin and PPI arise in people with T1D and discuss the recently described neoepitopes derived from the products of the insulin gene. Finally, we look forward to new approaches to deliver epitopes derived from PPI, PI and insulin that may allow immune tolerance to pancreatic beta cells to be restored in people with, or at risk of, T1D.
Topics: Animals; Autoantigens; Autoimmunity; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin-Secreting Cells
PubMed: 33524197
DOI: 10.1111/imcb.12442 -
Frontiers in Immunology 2020Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by recognition of pancreatic β-cell proteins as self-antigens, called autoantigens (AAgs),... (Review)
Review
Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease characterized by recognition of pancreatic β-cell proteins as self-antigens, called autoantigens (AAgs), followed by loss of pancreatic β-cells. (Pre-)proinsulin ([P]PI), glutamic acid decarboxylase (GAD), tyrosine phosphatase IA-2, and the zinc transporter ZnT8 are key molecules in T1D pathogenesis and are recognized by autoantibodies detected in routine clinical laboratory assays. However, generation of new autoantigens (neoantigens) from β-cells has also been reported, against which the autoreactive T cells show activity. Heat shock proteins (HSPs) were originally described as "cellular stress responders" for their role as chaperones that regulate the conformation and function of a large number of cellular proteins to protect the body from stress. HSPs participate in key cellular functions under both physiological and stressful conditions, including suppression of protein aggregation, assisting folding and stability of nascent and damaged proteins, translocation of proteins into cellular compartments and targeting irreversibly damaged proteins for degradation. Low HSP expression impacts many pathological conditions associated with diabetes and could play a role in diabetic complications. HSPs have beneficial effects in preventing insulin resistance and hyperglycemia in type 2 diabetes (T2D). HSPs are, however, additionally involved in antigen presentation, presenting immunogenic peptides to class I and class II major histocompatibility molecules; thus, an opportunity exists for HSPs to be employed as modulators of immunologic responses in T1D and other autoimmune disorders. In this review, we discuss the multifaceted roles of HSPs in the pathogenesis of T1D and in autoantigen-specific immune protection against T1D development.
Topics: Animals; Autoantigens; Autoimmune Diseases; Diabetes Mellitus, Type 1; Heat-Shock Proteins; Humans; T-Lymphocytes
PubMed: 33584694
DOI: 10.3389/fimmu.2020.612584 -
Immunology Oct 2023Autoreactive B cells are considered pathogenic drivers in many autoimmune diseases; however, it is not clear whether autoimmune B cells are invariably pathogenic or...
Autoreactive B cells are considered pathogenic drivers in many autoimmune diseases; however, it is not clear whether autoimmune B cells are invariably pathogenic or whether they can also arise as bystanders of T cell-driven autoimmune pathology. Here, we studied the B cell response in an autoantigen- and CD4 T cell-driven model of autoimmune hepatitis (AIH), the Alb-iGP_Smarta mouse in which expression of a viral model antigen (GP) in hepatocytes and its recognition by GP-specific CD4 T cells causes spontaneous AIH-like disease. T cell-driven AIH in Alb-iGP_Smarta mice was marked by autoantibodies and hepatic infiltration of plasma cells and B cells, particularly of isotype-switched memory B cells, indicating antigen-driven selection and activation. Immunosequencing of B cell receptor repertoires confirmed B cell expansion selectively in the liver, which was most likely driven by the hepatic GP model antigen, as indicated by branched networks of connected sequences and elevated levels of IgG antibodies to GP. However, intrahepatic B cells did not produce increased levels of cytokines and their depletion with anti-CD20 antibody did not alter the CD4 T cell response in Alb-iGP_Smarta mice. Moreover, B cell depletion did not prevent spontaneous liver inflammation and AIH-like disease in Alb-iGP_Smarta mice. In conclusion, selection and isotype-switch of liver-infiltrating B cells was dependent on the presence of CD4 T cells recognizing liver antigen. However, recognition of hepatic antigen by CD4 T cells and CD4 T cell-mediated hepatitis was not dependent on B cells. Thus, autoreactive B cells can be bystanders and need not be drivers of liver inflammation in AIH.
Topics: Mice; Animals; T-Lymphocytes; Hepatitis, Autoimmune; Autoantigens; Liver; Inflammation
PubMed: 37243425
DOI: 10.1111/imm.13665 -
BioEssays : News and Reviews in... Mar 2022The random nature of immunoglobulin gene segment rearrangement inevitably leads to the generation of self-reactive B cells. Avoidance of destructive autoimmune reactions...
The random nature of immunoglobulin gene segment rearrangement inevitably leads to the generation of self-reactive B cells. Avoidance of destructive autoimmune reactions is necessary in order to maintain physiological homeostasis. However, current central and peripheral tolerance concepts fail to explain the massive number of autoantibody-borne autoimmune diseases. Moreover, recent studies have shown that in physiological mouse models autoreactive B cells were neither clonally deleted nor kept in an anergic state, but were instead able to mount autoantibody responses. We propose that activation of autoreactive B cells is induced by polyvalent autoantigen complexes that can occur under physiological conditions. Repeated encounter of autoantigen complexes leads to the production of affinity-matured autoreactive IgM that protects its respective self-targets from degradation. We refer to this novel mechanism as adaptive tolerance. This article discusses the discovery of adaptive tolerance and the unexpected role of high affinity IgM autoantibodies.
Topics: Animals; Autoantibodies; Autoantigens; Autoimmunity; B-Lymphocytes; Clonal Anergy; Immune Tolerance; Immunoglobulin M; Mice
PubMed: 34984705
DOI: 10.1002/bies.202100236 -
Frontiers in Immunology 2023The DNA-binding peptide LL37 is a suspected autoantigen in psoriasis. It can be found in neutrophil extracellular traps (NETs) which have been suggested to play a role...
BACKGROUND
The DNA-binding peptide LL37 is a suspected autoantigen in psoriasis. It can be found in neutrophil extracellular traps (NETs) which have been suggested to play a role in the pathogenesis of the disease. Citrullination, the conversion of peptidyl-arginine into peptidyl-citrulline, can be implicated in the formation of NETs. We hypothesized that citrullination increases LL37 immunogenicity and that NETs are a source of LL37.
OBJECTIVES
We aimed to characterize cytokine responses of B cells and T cells to native and citrullinated LL37 (citLL37) and determine the prevalence and composition of circulating NETs in patients with psoriasis and healthy blood donors (HDs).
METHODS
Mononuclear cells (MNCs) and serum were isolated from 20 HDs and 20 patients with psoriasis. The MNCs were stimulated with native LL37 and citLL37 and the proportion of cytokine-positive B cells and T cells was determined by flow cytometry. Circulating antibodies against native LL37 and citLL37 as well as circulating NETs were measured by ELISA, as was the content of LL37, citLL37, and IgG in the NETs.
RESULTS
CitLL37, but not native LL37, induced IFN-γ-production by T cells and B cells from psoriasis patients, as well as IL-10-production by the patients' CD4 T cells. Serum from 40% of patients and 55% of HDs contained circulating NETs, of which 63% and 27%, respectively, contained LL37. Only two patients had NETs containing citLL37 and IgG antibodies were found in NETs from three patients and one HD. analysis of the cytokines produced by B cells and T cells after stimulation with citLL37 revealed two clusters of patients consisting of 10 high-responders and 9 low-responders. The high-responders were those that had circulating NETs in combination with an earlier age of onset of the disease.
CONCLUSION
Citrullinated but not native LL37 elicits IFN-γ-responses by T cells and B cells from psoriasis patients, particularly those with circulating NETs and early disease onset, suggesting a role of citLL37 as an autoantigen in this subgroup of patients.
Topics: Humans; Extracellular Traps; Psoriasis; Cytokines; Immunity; Immunoglobulin G; Autoantigens
PubMed: 38173716
DOI: 10.3389/fimmu.2023.1247592 -
Journal of Neuroimmunology May 2024Since the 1980s it is known that immune responses to the Epstein-Barr virus (EBV) are elevated in multiple sclerosis (MS) patients. Recent seroepidemiologial data have... (Review)
Review
Since the 1980s it is known that immune responses to the Epstein-Barr virus (EBV) are elevated in multiple sclerosis (MS) patients. Recent seroepidemiologial data have shown that this alteration after primary EBV infection identifies individuals with a more than 30-fold increased risk to develop MS. The mechanisms by which EBV infection might erode tolerance for the central nervous system (CNS) in these individuals, years prior to clinical MS onset, remain unclear. In this review I will discuss altered frequencies of EBV life cycle stages and their tissue distribution, EBV with CNS autoantigen cross-reactive immune responses and loss of immune control for autoreactive B and T cells as possible mechanisms. This discussion is intended to stimulate future studies into these mechanisms with the aim to identify candidates for interventions that might correct EBV specific immune control and/or resulting cross-reactivities with CNS autoantigens in MS patients and thereby ameliorate disease activity.
Topics: Humans; Multiple Sclerosis; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Animals; Autoantigens
PubMed: 38615370
DOI: 10.1016/j.jneuroim.2024.578343 -
Der Hautarzt; Zeitschrift Fur... Jun 2016Psoriasis is a human leukocyte antigen (HLA)-associated T‑cell-mediated disorder. (Review)
Review
BACKGROUND
Psoriasis is a human leukocyte antigen (HLA)-associated T‑cell-mediated disorder.
OBJECTIVES
The role of the main psoriasis risk allele HLA-C*06:02 in disease manifestation and the mechanisms which activate the pathogenic T‑cell response in the skin of psoriasis patients remained elusive.
MATERIALS AND METHODS
Key to the immune pathogenesis of psoriasis was the analysis of the specificity of the infiltrating lesional psoriatic CD8(+) T cells
RESULTS AND CONCLUSION
Analyses of the lesional psoriatic T‑cell reactivity demonstrate that psoriasis is an autoimmune disease. It is based on an autoimmune response against melanocytes which is preferentially mediated by HLA-C*06:02 through autoantigen presentation. Here we discuss the mechanisms of this autoimmune response in the context of the polygenic psoriatic predisposition.
Topics: Autoantigens; Autoimmune Diseases; HLA-C Antigens; Humans; Immunity, Innate; Models, Immunological; Psoriasis; Skin; T-Lymphocytes
PubMed: 27178039
DOI: 10.1007/s00105-016-3799-x -
Autoimmunity Sep 2018
Topics: Anti-Citrullinated Protein Antibodies; Autoantigens; Autoimmune Diseases; Extracellular Traps; Humans; Neutrophils
PubMed: 30994384
DOI: 10.1080/08916934.2018.1539839 -
Biologia Futura Mar 2021Autoimmune diseases are caused by breaking the central and/or peripheral tolerance against self, leading to uncontrolled immune response to autoantigens. The incidences... (Review)
Review
Autoimmune diseases are caused by breaking the central and/or peripheral tolerance against self, leading to uncontrolled immune response to autoantigens. The incidences of autoimmune diseases have increased significantly worldwide over the last decades; nearly 5% of the world's population is affected. The current treatments aim to reduce pain and inflammation to prevent organ damage and have a general immunosuppressive effect, but they cannot cure the disease. There is a huge unmet need for autoantigen-specific therapy, without affecting the immune response against pathogens. This goal can be achieved by targeting autoantigen-specific T or B cells and by restoring self-tolerance by inducing tolerogenic antigen-presenting cells (APC) and the development of regulatory T (Treg) cells, for example, by using autoantigenic peptides bound to nanoparticles. Transferring in vitro manipulated autologous tolerogenic APC or autologous autoantigen-specific Treg cells to patients is the promising approach to develop cellular therapeutics. Most recently, chimeric autoantibody receptor T cells have been designed to specifically deplete autoreactive B cells. Limitations of these novel autoantigen-specific therapies will also be discussed.
Topics: Animals; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Humans; Immune Tolerance; T-Lymphocytes; T-Lymphocytes, Regulatory
PubMed: 34554499
DOI: 10.1007/s42977-021-00074-4